Perovic S, Schröder H C, Pergande G, Ushijima H, Müller W E
Institut für Physiologische Chemie, Abteilung Angewandte Molekularbiologie, Universität, Mainz, Germany.
Exp Neurol. 1997 Oct;147(2):518-24. doi: 10.1006/exnr.1997.6559.
Flupirtine, trade name Katadolon, is a centrally acting nonopioid analgesic that has recently been found to display cytoprotective activity in vitro and in vivo on neurons induced to undergo apoptosis. This report shows that the PrP106-126 fragment of the prion protein, which is the likely etiological agent for a series of encephalopathies, is toxic to cortical neurons in vitro. Simultaneously, PrP106-126 influences the molecular GSH content and the bcl-2 expression in neurons. Significant toxicity (32% reduction in cell viability) was observed at a concentration of 50 microM of the peptide after 9 days of incubation, while at higher concentrations toxicity increased to 70%. Neurotoxicity was greatly reduced following coincubation with 1 to 3 microg/ml flupirtine. Concomitant with PrP106-126-mediated cytotoxicity, glutathione (GSH) content fell by > 70% with respect to untreated controls. This decrease in GSH level was strongly blocked by flupirtine under incubation conditions that reduce cell toxicity. In addition to normalizing GSH content, flupirtine induced the expression of the anti-apoptotically acting proto-oncogene bcl-2. Based on these in vitro data and on the favorable pharmacokinetic profile of the drug, we strongly suggest that flupirtine may prove useful for treatment of patients with prion disease.
氟吡汀，商品名为卡他多隆，是一种中枢性非阿片类镇痛药，最近发现它在体外和体内对诱导发生凋亡的神经元具有细胞保护活性。本报告表明，朊病毒蛋白的PrP106 - 126片段可能是一系列脑病的病因，在体外对皮质神经元有毒性。同时，PrP106 - 126会影响神经元中分子谷胱甘肽（GSH）含量和bcl - 2表达。孵育9天后，在肽浓度为50 microM时观察到显著毒性（细胞活力降低32%），而在更高浓度下毒性增加到70%。与1至3微克/毫升氟吡汀共同孵育后，神经毒性大大降低。与PrP106 - 126介导的细胞毒性同时发生的是，与未处理的对照相比，谷胱甘肽（GSH）含量下降了> 70%。在降低细胞毒性的孵育条件下，氟吡汀强烈阻断了GSH水平的这种下降。除了使GSH含量正常化外，氟吡汀还诱导了具有抗凋亡作用的原癌基因bcl - 2的表达。基于这些体外数据以及该药物良好的药代动力学特征，我们强烈建议氟吡汀可能被证明对治疗朊病毒病患者有用。
